Disorders of cognition are generally characterized by one or more mental symptoms such as forgetfulness, confusion, memory loss, attentional deficits or affective or emotional disturbances. These symptoms may arise as a result of the natural aging process or from organic brain disease, cerebrovascular disease, head injury or developmental or genetic defects. Although cognitive disorders often accompany the general aging process, presenile and senile primary degenerative dementia are the most commonly accepted causes of mental deterioration in the elderly.
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons at any age. The N-methyl-D-aspartate (NMDA) sub-type of the glutamate receptor is a ligand-gated ion channel involved in excitatory neurotransmission in the mammalian central nervous system. For example, over-stimulation of the NMDA receptor results in the neuronal excitotoxicity important in the pathophysiology of epilepsy and ischemia-induced neuron death. Separate regulatory sites on the NMDA receptor-channel complex include the binding site for the agonist L-glutamate, a high-affinity binding site for the obligatory co-agonist glycine, a site where Zn ions act to allosterically inhibit the agonist-induced response independently of membrane potential, a site(s) within the channel wherein Mg ions and phencyclidines such as (+)-5-methyl-10,11-dihydro-5H-dibenzoa,d!cyclohepten-5,10-imine (MK-801) bind to produce a voltage-dependent open channel block and a distinct binding site for the naturally occurring polyamines, spermine and spermidine.
The polyamine site may exert either agonistic or antagonistic modulatory activity depending on the polyamine concentration, as well as on the chemical structure of the polyamine Williams et al., Neuron., Vol. 5, pp. 199-208 (1990); Williams et al., Life Sci., Vol. 48, pp. 469-498 (1991)!. Agonists like spermine allosterically facilitate functioning of the L-glutamate and glycine sites resulting in increased binding of .sup.3 H!MK-801 compared to that seen in the presence of maximal amounts of L-glutamate and glycine alone. Several compounds that protect neurons from excitotoxicity appear to act as antagonists at the polyamine site Carter et al., J. Pharmacol. Exp. Ther., Vol. 253, pp. 475-482 (1990); Zeevalk et al., Brain Res., Vol. 522, pp. 135-139 (1990)!.
One hypothesis regarding the mechanism of the memory impairment seen in cognitive disorders such as Alzheimer's Disease (AD), the "glutamate hypothesis," suggests that loss of neurotransmission in a glutamatergic system accounts for memory impairment Greenamyre et al., Neurobiol. Aging, Vol. 10, pp. 593-602 (1989)!. While the exact etiology of AD is not clear, both the level of naturally occurring polyamines and the activity of S-adenosylmethionine decarboxylase, an enzyme important in the biosynthesis of the polyamines, is increased in the brains of AD patients when compared with matched, normal controls Morrison and Kish, "Brain Polyamine Levels Are Altered in Alzheimer's Disease," Neurosci. Lett., (November 1995); Morrison et al., Neurosci. Lett., Vol. 154, pp. 141-144 (1993)!. Since the natural polyamines can enhance NMDA-mediated excitatory damage by action at the NMDA receptor-channel complex, this increased brain polyamine concentration may be one of the causes of AD.
A major pathological characteristic of AD within the brain is the increased number of amyloid-containing senile plaques having dense cores composed primarily of highly insoluble aggregates of .beta.-amyloid peptide (.beta.A). Transglutaminase enzymes facilitate the formation of insoluble polymers of the .beta.-amyloid peptide Dudek et al., Brain Res., Vol. 651, pp. 129-133 (1994)!. The naturally occurring polyamines, spermine, spermidine and putrescine, have been shown to be essential to protein cross-linking by transglutaminases in other mammalian systems Romijn, Andrologia, Vol. 22, Suppl. 1, pp. 83-91 (1990)!. Unusual concentrations of the naturally occurring polyamines in the brains of AD patients may also influence the formation of the senile plaques characteristic of AD and similar dementias.
Only one pharmaceutical composition is currently licensed in the United States as a treatment for Alzheimer's Disease, 9-amino-1,2,3,4-tetrahydroacridine (tacrine). The therapeutic use of tacrine is based upon its activity as an acetylcholinesterase inhibitor, which can increase the availability of acetylcholine as a neurotransmitter. Use of this drug suffers from several drawbacks including limited efficacy and hepatotoxicity Kaul, J. Pharm. Pharmacol., Vol. 14, pp. 237-242 (1962); Summers et al., New Engl. J. Med., Vol. 315, pp. 1241-1245 (1986)!. Thus, it is of interest to develop novel compositions and methods that are useful for the treatment of Alzheimer's disease and other neurodegenerative conditions.